Pregnancy involves anatomical, physiological and biochemical adaptations that are important to provide proper fetal nutrition ^[1][12].

Carbohydrate metabolism in pregnancy is complex and not fully understood. The resultsare, primarily, changes in the hormonal balance during pregnancy and the formation of a new “glucose feto-placental shunt”. On the other hand, during pregnancy, the body’s response to glucose load changes, i.e., an insulin resistance appears, most likely under the influence of resistin (Retn) is a pro-inflammatory adipokine, which has been identified as an “adipose-tissue-specific secretory factor” (ADSF), and it was eventually renamed “resistin” (or “resistance to insulin”) ^[2][13].

The secretion of hormones that affect glucose metabolism changes qualitatively and quantitatively during pregnancy. In addition to these factors, the metabolism is influenced by the placenta through the production of estrogen, progesterone and hPL. The main energy substance for the fetus is glucose, which passes the placental barrier by facilitated diffusion ^[3][14].

At the beginning of the pregnancy, thwe researchers find hypoglycemia with hypoinsulinemia and an increased turnover of amino acids. This is explained by intensive processes of glycogenesis and lipogenesis, with the accumulation of subcutaneous fatty tissue inpregnant women. Adiponectin is secreted by adipocytes, and it has multiple roles in the stimulation of lipid metabolism, glucose uptake, it displays anti-inflammatory properties and it correlates inversely with body weight and fat mass. During pregnancy, the adiponectin concentration drops due to an increase in the fat mass, and it has been negatively correlated with birth weight, suggesting that adiponectin may be involved in placental nutrient transport ^[4][15].

Leptin is secreted by fat cells and the placenta, and it participates in regulating food intake, energy homeostasis, insulin secretion, as well as the transport of nutrients to the fetus ^[5][16]. The amount of insulin increases during pregnancy. The most important diabetogenic effect in pregnancy is hPL, which is biochemically similar to the growth hormone and whose production increases during pregnancy, reducing the oxidation of glucose in the cell. This hormone acts anabolically on the proteins and lipolytically on the fats (increases the concentration of free fatty acids), despite increased lipogenesis. hPL is produced independently of glycemia, in contrast to growth hormone, whose production decreases with hyperglycemia, and vice versa ^[6][17].

Cholesterol and triacylglycerol decrease most often in the first seven weeks of pregnancy, and then, they increase until the end of pregnancy. There is a hypothesis that the increase in the concentration of free fatty acids (FFA) in the blood of pregnant women duringadvanced pregnancy is the result of a decrease in the sensitivity of insulin to the concentration of glucose in the blood. In pregnant women, there is a physiological increase in their body weight and a change in the fat metabolism ^[7][18].

Excessiveadipose tissue AT accumulation is characterized by the dysregulation of adipokine release, including leptin, adiponectin, and resistin ^[8][19].Excessive AT generates an imbalance between the prooxidative, and antioxidative systems that usually results in anincrease in the number of reactive oxygen species (ROS) ^[9][20]. While low ROS levels are essential to maintaining diverse physiological functions, excessive ROS production alters different cellular components such as proteins, lipids and DNA, generating oxidized biomolecules that function as the biomarkers of oxidative damage. The elevation of malondialdehyde (MDA), carbonylated proteins (CP) and oxidized base 8-oxo-2′-deoxyguanosine (8-oxodG) as indicators of lipid peroxidation, protein and DNA oxidation, respectively, hasdeleterious effects on the cells ^[10][21].

During pregnancy, the symptoms of COVID-19 are similar to the symptoms of it in non-pregnant women. Severe pneumonia occurred in from 0 to 14% of them ^[11][22]. Acute respiratory distress syndrome (ARDS) occurred when fluid built up in the alveoli of the lungs.Accumulated fluid in the alveoli prevents proper breathing and the supply of air to the lungs, and thus, insufficient oxygenation of the blood stream. In this way, the complete hypoxia of all of the organs occurs, especially in the heart and brain. ARDS occurs most often in pregnant women who have comorbidities (diabetes mellitus, chronic hypertension, chronic kidney disease, cardiovascular disease and previous brain and heart infarctions) usually within a few hours or days of the infection ^[12][23]. The respiratory distress syndrome ina pregnant woman can affect the supply of oxygen to the fetus and initiate the mechanism of metabolic disorders of the fetus and newborns, which are caused by asphyxia ^[13][24]. In the absence of oxygen in utero in the placenta, the microcirculation is disturbed, which causes a metabolic disorder in the mother–fetus system because there is a disturbance in the exchange of nutrients, and later, also a disturbance in the transport of oxygen. Oxidative stress (OA) is defined as the excessive formation and/or insufficient removal of free radicals and their products due to an impairment of the anti-oxidative (AO) capacities. As a consequence, proteins, DNA, lipids and other biomolecules are damaged, which leads to pathological changes in the body. Protein oxidation can be twofold: the free radicals can act directly on the protein or indirectly as a result of the oxidation of other molecules (lipids or carbohydrates). The oxidative modification of DNA is most pronounced in the presence of a metal that has a variable valence, and then, OH• is formed as a product of the oxidative reaction. The resulting radical reacts with the purine base guanine, and 8-hydroxydeoxyguanosine (8-OHdG) is formed, which is an indicator of oxidative DNA damage ^[8][19]. Leukotrienes and prostaglandins formed from arachidonic acid and free oxygen radicals increasethe microvascular permeability, which leads to the transendothelial migration of leukocytes and their infiltration into ischemic brain tissue and the activation of the inflammatory reaction. The result is the further release of a large amount of oxygen free radicals (OFR): superoxide anions, hydrogen peroxide and hydroxyl radicals. OFRs worsen the tissue damage and biochemical functioning of the cells, causing the peroxidation of the lipid component of the cell membrane and a further effect on the cell lipids, proteins and nucleic acids, which enables the invasion and infiltration of neutrophils into the post-ischemic brain tissue. NO synthetase increases the NO concentration, and an abnormally high amount of superoxide converts NO to peroxynitrite, which damages the capillary endothelium and increases not only edema, but also leads to endothelial protrusions that further block the capillaries. Neuroinflammation and oxidative stress (OS) can initiate a cascade of events, leading to lipid, protein and deoxyribonucleic acid (DNA) damage, cellular dysfunction and ultimately, fetal death ^[7][18].

The adipose tissue actsin a similar way to active endocrine tissuewell as an energy storage site. In addition, it creates adipokines and leptin that impact the immune response ^[14][25]. Visceral adipose tissue (VAT) appears to be more pathogenic than the subcutaneous depots do due to adipocyte hypertrophy, leading to local compression and hypoxia, which results in oxidative stress, cell apoptosis and necrosis ^[15][26].

In this way, the immune cells are activated, eliciting both a local and systemic low-grade inflammatory statewhich is characterized by moderately elevated levels of C-reactive protein (CRP) and pro-inflammatory cytokines such as TNF-α and IL-6, as well as a slightly increased number of pro-inflammatory neutrophils and mast cells and a decreased number of anti-inflammatory natural killer T cells and eosinophils. Therefore, it is not surprising that visceral adiposity has been associated with a higher risk of severe COVID-19 cases ^[16][27]. Cell membrane cholesterol plays an important role in viral infections, constantly interacting with high-density lipoproteincholesterol (HDL-C) and low-density lipoproteincholesterol (LDL-C). Low serum lipid levels in severe COVID-19 cases are due to an acute inflammatory response. In addition, HDL-C, LDL-C and triglyceride (TG) levels transiently decreased at the time of the COVID-19 diagnosis and later, they returned to the pre-infection levels two months after the SARS-CoV-2 infection. HDL is of particular importance in viral infections, especially SARS-CoV-2 infection. HDL consumption has been shown to impair its antiviral activity. Lipid rafts, which are cholesterol-rich microdomains on the host cell membranes, play a vital role in viral entry and budding. LDL promotes lipid raft formation, and it is possible that HDL depletes the cholesterol in the lipid rafts through cholesterol efflux from the cells. The depletion of cell membrane cholesterol reduced the risk of anSARS-CoV-2 infection by reducing the turnover of ACE2 and furin protease in the lipid rafts. In addition, scavenger receptor protein-B1 (SR-B1), which is an HDL receptor, has been shown to facilitate the ACE2-dependent entry of SARS-CoV-2. Lower HDL-C concentrations promote SRB1-mediated SARS-CoV-2 infections, whereas higher HDL-C concentrations inhibit SARS-CoV-2 infections. Apo-A1, an important component of HDL, has been shown to inhibit virus fusion and its entry into the host cells. Taken together, these data support the ouresearchers' findings that increased serum HDL-C levels may be protective against an SARS-CoV-2 infection ^[17][28].

The discharge of the free radicals of oxygen such ashydrogen peroxide and superoxide anion by the polymorphonuclear cells and neutrophils is influenced by an increase in the amount of leptin. Leptin can also influence neutrophil migration by activating p38mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (Src) and increasing tumor necrosis factor-alpha (TNF-a) production by monocytes, while decreasing the chemotaxis process by blocking interleukin-8 (IL-8) ^[18][29]. As it is a member of the MAPK signaling family, p38 is largely associated with cellular stress responses and apoptosis. Anincreased amount of leptin causes an increase in the neutrophilic lung inflammation, and SARS-CoV-2 can cause critical ARDS ^[19][30].

Adipose tissue macrophages are referred to as classically activated (M1) macrophages. They release cytokines such as IL-1β, IL-6 and TNFα, creating a pro-inflammatory environment that blocks adipocyte insulin action, contributing to the development of IR and type 2 diabetes mellitus. In lean individuals, the macrophages are in an alternatively activated (M2) state. M2 macrophages are involved in wound healing and immunoregulation. Wound-healing macrophages play a major role in tissue repair and homoeostasis, while immunoregulatory macrophages produce IL-10, an anti-inflammatory cytokine, which may protect against inflammation. The functional role of Tcell accumulation has recently been characterized in adipose tissue. Cytotoxic Tcells are effector Tcells and have been implicated in macrophage differentiation, activation and migration ^[20][21][31,32]. These two hormones are crucial in the development of severe COVID-19 infections in people with inflammation because they are disrupted in obesity. Leptin and insulin resistance affect Tcell function in a reduced Tcell response to infection ^[22][33].

Macrophages in an activated state cause the death of the endothelial cells by the process of apoptosis or the secretion of proteolytic enzymes. The apoptotic effect of oxidized low-density lipoproteins (Ox-LDL) on endothelial cells can be attributed to the oxidation products of phosphatidylcholine or oxysterol. Under conditions of hypoxia, the oxidation of lipids occurs, especially polyunsaturated fatty acids (PUFA) and cholesterol. Oxysterols as cholesterol oxidation products are a diagnostic biomarker of oxidative stress ^[23][34]. The increased concentration of LDL particles in the bloodstream causes the person to become susceptible to a modification by the reactive oxygen and nitrogen particles, which are products of normal cellular metabolism. Endothelial cells, smooth muscle cells and macrophages are the main source of oxidizing particles for the oxidative modification of macromolecules in the subendothelium. In the early phase, mild oxidation leads to the formation of minimally modified LDL in the subendothelial space as a result of the peroxidation of unsaturated fatty acids in phospholipids and the oxidation of lecithin. Modified LDL particles are proinflammatory because they stimulate the production of signaling molecules and growth factors (vascular adhesion molecule-1, VCAM-1, monocyte chemotactic protein-1, MCP-1, and monocyte colony-stimulating factor, M-CSF) whichinfluence the movement of circulating monocytes and Tlymphocytes and their infiltration into the subendothelium of the blood vessels and inflammation. There is also the proliferation and differentiation of the monocytes into macrophages ^[19][30].

Further oxidation leads to the modification of lysine residues on apoB-100, which are crucial for the recognition of LDL by specific receptors. This leads to a decreased affinity of LDL particles for the LDL receptors. Over time, the LDL particles are so modified (glycosylated, ox-LDL or in the form of so-called advanced glycosylation end products—Advanced Glycosylation Endproducts, AGE particles) that they can no longer be introduced to the macrophages via the LDLreceptor, but rather, this occurs via the scavenger receptors. The characteristic of this receptor pathway is that there is no downstream regulation of the receptor, and no blockade of intracellular cholesterol synthesis by the inhibition of the enzyme HMG-CoA reductase. With the uncontrolled intake of ox-LDL, the macrophages accumulate cholesterol ester and lipid peroxides, and they pass into the so-called foamy cells ^[21][32].

Oxidatively modified LDL particles (Oh-LDL) can also be created by direct oxidation, which mainly takes place on unsaturated fatty acids under the influence of superoxide and peroxynitrite radicals, or by the transfer of already oxidized cellular lipids to low-density lipoproteins (LDL) ^[24][35]. In doing so, lipid peroxides are formed, which enter into a new chain reaction, as well as conjugated dienes and aldehyde products. These changes are preceded by a “hesitation period” of aldehyde oxidation, i.e., a latent period in which the antioxidants in LDL are consumed, after which the oxidation of the fatty acids begins. Degraded LDL simultaneously becomes a ligand for the receptors/catchers of the macrophages, and in this way monocytes are attracted to the site of the lesion, “take” lipoproteins and gradually turn into foam cells. When the LDL deposits exceed a critical threshold, the excessive activation of complement and macrophages creates the conditions for chronic inflammation ^[25][36]. Proinflammatory oxidatively modified LDL particles inhibit endothelial nitric oxide synthase (eNOS), leading to vasoconstriction by reducing the amount of available nitric oxide (NO). They damage the endothelial cells, and this leads to the apoptosis and necrosis of the vascular cells, all of which leads to the “leakage” of cellular lipids and lysosomal enzymes. There is a proliferation of macrophages and smooth muscle cells, the synthesis and secretion of numerous growth factors and pro-inflammatory cytokines from the surrounding cells, and the aggregation of the platelets. Additionally, these changed particles affect the retention of the macrophages in the arterial wall, inhibiting their mobility. The production of free radicals that intensify the oxidation of LDL is also increased. The cytotoxic effect leads to an increase in the concentration of calcium in the endothelial cells, and this process starts endothelial dysfunction. The foamy cells decay over time, and the lipid core of the atheromatous plaque is formed from the cellular detritus ^[22][33].

Specific arterial sites, such as forks and bends, lead to the accumulation of excess circulating LDL, endothelial damage at these sites, and changes in the blood flow. Specific molecules responsible for the adhesion, migration and accumulation of monocytes and Tlymphocytes are expressed in these places in the endothelium. Changes in blood flow alter the expression of the genes that provide information for the synthesis of adhesion molecules. Changes in the blood flow determine the location of the damage in the artery wall ^[23][34].

The inflammation process occurs in the intima of the blood vessels, and this is followed by the accumulation of macrophages, i.e., foam cells and T lymphocytes, which create a predisposition for long-term inflammation which manifests as a long-term COVID effect ^[26][37].